1. It was discovered in the P.I.'s laboratory that mevalonate, a key intermediate in cholesterol biosynthesis, was metabolized in vivo (and in vitro) on pathways that do not lead to sterols, but transfer mevalonate carbons to the two-carbon pool. It is the aim of the current work to elucidate the intermediary stages of the latter transformations of mevalonate in model systems of liver and kidney slices and homogenates and, particularly, by "pulse-labelling" in vivo of kidneys, which are responsible for over one-half of the "shunting" of mevalonate carbons away from sterol synthesis. 2. Model alkylphosphonates and phosphonophosphates proved to be strong inhibitors of farnesyl-PP synthetase. Further phosphonate and phosphonophosphate analogues of substrates of farnesylpyrophosphate synthetase will be synthesized and tested as enzyme inhibitors and as possible "anticholesterol" agents. 3. We believe that we have obtained a truly soluble form of presqualene and squalene synthetases, enzymes attached to microsomes derived from endoplasmic reticulum. The lowest molecular weight unit of these enzymes is 52,000 Daltons. We are trying to ascertain whether this low molecular weight unit is active by itself, or only after its reaggregation to a high molecular weight complex. Specific inhibitors to these enzymes have already been made by us, and further inhibitors will be synthesized. BIBLIOGRAPHIC REFERENCES: Abnormal efflux of cholesterol from heterozygous familial hypercholesterolemic leukocytes. A.M. Fogelman, J. Seager, J. Edmond and G. Popjak, Circulation, 52: Suppl. II, 11-81,1975. A direct relationship between the amount of sterol lost from rat hepatocytes and the increase in activity of HMG-CoA reductase. P.A. Edwards, A.M. Fogelman and G. Popjak, Biochem. Biophys. Res. Commun. 68, 64, 1976.